Imperial College London

DrTomCole

Faculty of MedicineNational Heart & Lung Institute

Clinical Project Manager
 
 
 
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Contact

 

+44 (0)20 3313 6198t.cole

 
 
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Location

 

NIHR Imperial CRF, Room G20ICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

26 results found

Win Z, Weiner J, Listanco A, Patel N, Sharma R, Greenwood A, Maertzdorf J, Mollenkopf H-J, Pizzoferro K, Cole T, Bodinham CL, Kaufmann SHE, Denoel P, Del Giudice G, Lewis DJMet al., 2021, Systematic evaluation of kinetics and distribution of muscle and lymph node activation measured by F-18-FDG- and C-11-PBR28-PET/CT imaging, and whole blood and muscle transcriptomics after immunization of healthy humans with adjuvanted and unadjuvanted vaccines, Frontiers in Immunology, Vol: 11, Pages: 1-16, ISSN: 1664-3224

Systems vaccinology has been applied to detect signatures of human vaccine induced immunity but its ability, together with high definition in vivo clinical imaging is not established to predict vaccine reactogenicity. Within two European Commission funded high impact programs, BIOVACSAFE and ADITEC, we applied high resolution positron emission tomography/computed tomography (PET/CT) scanning using tissue-specific and non-specific radioligands together with transcriptomic analysis of muscle biopsies in a clinical model systematically and prospectively comparing vaccine-induced immune/inflammatory responses. 109 male participants received a single immunization with licensed preparations of either AS04-adjuvanted hepatitis B virus vaccine (AHBVV); MF59C-adjuvanted (ATIV) or unadjuvanted seasonal trivalent influenza vaccine (STIV); or alum-OMV-meningococcal B protein vaccine (4CMenB), followed by a PET/CT scan (n = 54) or an injection site muscle biopsy (n = 45). Characteristic kinetics was observed with a localized intramuscular focus associated with increased tissue glycolysis at the site of immunization detected by 18F-fluorodeoxyglucose (FDG) PET/CT, peaking after 1–3 days and strongest and most prolonged after 4CMenB, which correlated with clinical experience. Draining lymph node activation peaked between days 3–5 and was most prominent after ATIV. Well defined uptake of the immune cell-binding radioligand 11C-PBR28 was observed in muscle lesions and draining lymph nodes. Kinetics of muscle gene expression module upregulation reflected those seen previously in preclinical models with a very early (~6hrs) upregulation of monocyte-, TLR- and cytokine/chemokine-associated modules after AHBVV, in contrast to a response on day 3 after ATIV, which was bracketed by whole blood responses on day 1 as antigen presenting, inflammatory and innate immune cells trafficked to the site of immunization, and on day 5 associated with activated CD4+ T cells. These observat

Journal article

Folegatti PM, Ewer KJ, Aley PK, Angus B, Becker S, Belij-Rammerstorfer S, Bellamy D, Bibi S, Bittaye M, Clutterbuck EA, Dold C, Faust SN, Finn A, Flaxman AL, Hallis B, Heath P, Jenkin D, Lazarus R, Makinson R, Minassian AM, Pollock KM, Ramasamy M, Robinson H, Snape M, Tarrant R, Voysey M, Green C, Douglas AD, Hill AVS, Lambe T, Gilbert SC, Pollard AJ, Oxford COVID Vaccine Trial Groupet al., 2020, Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial., The Lancet, Vol: 396, Pages: 467-478, ISSN: 0140-6736

BACKGROUND: The pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might be curtailed by vaccination. We assessed the safety, reactogenicity, and immunogenicity of a viral vectored coronavirus vaccine that expresses the spike protein of SARS-CoV-2. METHODS: We did a phase 1/2, single-blind, randomised controlled trial in five trial sites in the UK of a chimpanzee adenovirus-vectored vaccine (ChAdOx1 nCoV-19) expressing the SARS-CoV-2 spike protein compared with a meningococcal conjugate vaccine (MenACWY) as control. Healthy adults aged 18-55 years with no history of laboratory confirmed SARS-CoV-2 infection or of COVID-19-like symptoms were randomly assigned (1:1) to receive ChAdOx1 nCoV-19 at a dose of 5 × 1010 viral particles or MenACWY as a single intramuscular injection. A protocol amendment in two of the five sites allowed prophylactic paracetamol to be administered before vaccination. Ten participants assigned to a non-randomised, unblinded ChAdOx1 nCoV-19 prime-boost group received a two-dose schedule, with the booster vaccine administered 28 days after the first dose. Humoral responses at baseline and following vaccination were assessed using a standardised total IgG ELISA against trimeric SARS-CoV-2 spike protein, a muliplexed immunoassay, three live SARS-CoV-2 neutralisation assays (a 50% plaque reduction neutralisation assay [PRNT50]; a microneutralisation assay [MNA50, MNA80, and MNA90]; and Marburg VN), and a pseudovirus neutralisation assay. Cellular responses were assessed using an ex-vivo interferon-γ enzyme-linked immunospot assay. The co-primary outcomes are to assess efficacy, as measured by cases of symptomatic virologically confirmed COVID-19, and safety, as measured by the occurrence of serious adverse events. Analyses were done by group allocation in participants who received the vaccine. Safety was assessed over 28 days after vaccination. Here, we report the preliminary findings on safety, reactogenicity, and

Journal article

Sharma R, Valls PO, Inglese M, Dubash S, Chen M, Gabra H, Montes A, Challapalli A, Arshad M, Tharakan G, Chambers E, Cole T, Lozano-Kuehne JP, Barwick TD, Aboagye EOet al., 2020, [18F]Fluciclatide PET as a biomarker of response to combination therapy of pazopanib and paclitaxel in platinum-resistant/refractory ovarian cancer, European Journal of Nuclear Medicine and Molecular Imaging, Vol: 47, Pages: 1239-1251, ISSN: 0340-6997

BACKGROUND: Angiogenesis is a driver of platinum resistance in ovarian cancer. We assessed the effect of combination pazopanib and paclitaxel followed by maintenance pazopanib in patients with platinum-resistant/refractory ovarian cancer. Integrins αvβ3 and αvβ5 are both upregulated in tumor-associated vasculature. [18F]Fluciclatide is a novel PET tracer that has high affinity for integrins αvβ3/5, and was used to assess the anti-angiogenic effect of pazopanib. PATIENTS AND METHODS: We conducted an open-label, phase Ib study in patients with platinum-resistant/refractory ovarian cancer. Patients received 1 week of single-agent pazopanib (800 mg daily) followed by combination therapy with weekly paclitaxel (80 mg/m2). Following completion of 18 weeks of combination therapy, patients continued with single-agent pazopanib until disease progression. Dynamic [18F]fluciclatide-PET imaging was conducted at baseline and after 1 week of pazopanib. Response (RECIST 1.1), toxicities, and survival outcomes were recorded. Circulating markers of angiogenesis were assessed with therapy. RESULTS: Fourteen patients were included in the intention-to-treat analysis. Complete and partial responses were seen in seven patients (54%). Median progression-free survival (PFS) was 10.63 months, and overall survival (OS) was 18.5 months. Baseline [18F]fluciclatide uptake was predictive of long PFS. Elevated baseline circulating angiopoietin and fibroblast growth factor (FGF) were predictive of greater reduction in SUV60,mean following pazopanib. Kinetic modeling of PET data indicated a reduction in K1 and Ki following pazopanib indicating reduced radioligand delivery and retention. CONCLUSIONS: Combination therapy followed by maintenance pazopanib is effective and tolerable in platinum-resistant/refractory ovarian cancer. [18F]Fluciclatide-PET uptake parameters predict clinical outcome with pazopanib therapy indicating an anti

Journal article

Pinato DJ, Cole T, Bengsch B, Tait P, Sayed AA, Abomeli F, Gramenitskaya D, Allara E, Thomas R, Ward C, Wong CN, Akarca AU, Blanco JM, Marafioti T, Marchesi J, Sharma Ret al., 2020, 750P - A phase Ib study of pembrolizumab following trans-arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): PETAL, Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) / Liver Meeting, Publisher: Wiley, Pages: 209A-210A, ISSN: 0270-9139

BackgroundThe efficacy of TACE is secondary to its dual ischaemic and cytotoxic effect, which promotes immunogenic tumor cell death. TACE may prime adaptive immunity and facilitate pembrolizumab (pembro; anti-PD1) in promoting tumour immune rejection and improve outcome in HCC. We designed this phase Ib study to evaluate safety, preliminary activity of TACE+pembrolizumab and explore mechanisms of efficacy.MethodsUp to 32 patients (pts) with intermediate-stage HCC were planned to receive up to 2 rounds of conventional TACE followed by pembro 200 mg q3w 30 days post-TACE until disease progression or unacceptable toxicity for up to 1 year. Primary endpoint was safety with dose-limiting toxicities emerging from the combination being evaluated over a 21-days window from commencement of pembro. Secondary endpoints included PFS rates q12w. We explored tumour and host determinants of response in tissue, blood and stool samples to confirm the bioactivity of the combination.ResultsIn cohort 1 (n = 6) patients were all of BCLC-B stage, 83% males, 16% HCV-positive, 50% ECOG PS 0, median age 62 years. Child-Pugh (CP) was A in 5 and B7 in 1 pt. Median tumour size was 4 cm, and median number of lesions was 2. All-grade adverse events potentially related to treatment (tx) occurred in 50% of pts including diarrhoea (n = 1, G3), skin rash (n = 2, G2), infusion reaction (n = 1, G2) and adrenal insufficiency (n = 1, G2). Pembro yielded no synergistic toxicity with TACE and no DLTs were reported. At data cut-off, tx was ongoing for 3 pts with a median duration of tx of 2.8 months. Of the 4 radiologically evaluable patients, 3 had stable disease on pembro, 1 had progressive disease. Cause of withdrawal included disease progression/death (n = 2) and worsening liver failure in the CP B7 pt, non tx-related (n = 1). Updated data from an expanded pt cohort will be shown and efficacy data will be correlated with T-cell responses to recognized tumor-associated antigens, tumour-infiltrating lymp

Conference paper

Pinato DJ, Cole T, Bengsch B, Tait P, Sayed AA, Aborneli F, Gramenitskaya D, Allara E, Thomas R, Ward C, Wong CN, Akarca AU, Blanco JM, Marafioti T, Marchesi J, Sharma Ret al., 2019, A phase Ib study of pembrolizumab following trans-arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): PETAL, 44th Congress of the European-Society-for-Medical-Oncology (ESMO), Publisher: OXFORD UNIV PRESS, Pages: 288-288, ISSN: 0923-7534

Conference paper

Sharma R, Valls PO, Inglese M, Dubash S, Chen M, Gabra H, Montes A, Challapalli A, Arshad M, Thakaran G, Chambers E, Cole T, Lozano-Kuehne J, Barwick TD, Aboagye EOet al., 2019, [F-18]fluciclatide Pet As A Biomarker Of Response To Combination Therapy Of Pazopanib And Paclitaxel In Platinum-resistant/refractory Ovarian Cancer, 32nd Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), Publisher: SPRINGER, Pages: S223-S223, ISSN: 1619-7070

Conference paper

Abraham S, Juel HB, Bang P, Cheeseman HM, Dohn RB, Cole T, Kristiansen MP, Korsholm KS, Lewis D, Olsen AW, McFarlane LR, Day S, Knudsen S, Moen K, Ruhwald M, Kromann I, Andersen P, Shattock RJ, Follmann Fet al., 2019, Safety and immunogenicity of the chlamydia vaccine candidate CTH522 adjuvanted with CAF01 liposomes or aluminium hydroxide: a first-in-human, randomised, double-blind, placebo-controlled, phase 1 trial, Lancet Infectious Diseases, Vol: 19, Pages: 1091-1100, ISSN: 1473-3099

BACKGROUND: Chlamydia is the most common sexually transmitted bacterial infection worldwide. National screening programmes and antibiotic treatment have failed to decrease incidence, and to date no vaccines against genital chlamydia have been tested in clinical trials. We aimed to assess the safety and immunogenicity, in humans, of a novel chlamydia vaccine based on a recombinant protein subunit (CTH522) in a prime-boost immunisation schedule. METHODS: This phase 1, first-in-human, double-blind, parallel, randomised, placebo-controlled trial was done at Hammersmith Hospital in London, UK, in healthy women aged 19-45 years. Participants were randomly assigned (3:3:1) to three groups: CTH522 adjuvanted with CAF01 liposomes (CTH522:CAF01), CTH522 adjuvanted with aluminium hydroxide (CTH522:AH), or placebo (saline). Participants received three intramuscular injections of 85 μg vaccine (with adjuvant) or placebo to the deltoid region of the arm at 0, 1, and 4 months, followed by two intranasal administrations of 30 μg unadjuvanted vaccine or placebo (one in each nostril) at months 4·5 and 5·0. The primary outcome was safety and the secondary outcome was humoral immunogenicity (anti-CTH522 IgG seroconversion). This study is registered with Clinicaltrials.gov, number NCT02787109. FINDINGS: Between Aug 15, 2016, and Feb 13, 2017, 35 women were randomly assigned (15 to CTH522:CAF01, 15 to CTH522:AH, and five to placebo). 32 (91%) received all five vaccinations and all participants were included in the intention-to-treat analyses. No related serious adverse reactions were reported, and the most frequent adverse events were mild local injection-site reactions, which were reported in all (15 [100%] of 15) participants in the two vaccine groups and in three (60%) of five participants in the placebo group (p=0·0526 for both comparisons). Intranasal vaccination was not associated with a higher frequency of related local reactions (reported in seven [47%]

Journal article

Sharma R, Valls PO, Inglese M, Dubash SR, Chen M, Gabra H, Montes A, Challapalli A, Tharakan G, Chambers E, Cole T, Lozano-kuehne J, Barwick T, Aboagye Eet al., 2019, [18F] Fluciclatide PET as a biomarker of clinical response to combination therapy of pazopanib and paclitaxel in patients with platinum-resistant or platinum-refractory advanced ovarian cancer: Results of a phase Ib study., Journal of Clinical Oncology, Vol: 37, Pages: 3070-3070, ISSN: 0732-183X

Journal article

Cheeseman H, Day S, McFarlane L, Fleck S, Miller A, Cole T, Cope A, Tolazzi M, Hannaman D, Kratochvil S, McKay P, Kent S, Chung A, Cook A, Scarlatti G, Combadiere B, Abraham S, McCormack S, Lewis D, Shattock Ret al., 2018, Combined Skin and Muscle DNA Priming Provides Enhanced Humoral Responses to an HIV-1 Clade C Envelope Vaccine, HIV Research for Prevention Meeting (HIVR4P) - AIDS Vaccine, Microbicide and ARV-Based Prevention Science, Publisher: MARY ANN LIEBERT, INC, Pages: 43-43, ISSN: 0889-2229

Conference paper

Cheeseman HM, Day S, McFarlane LR, Fleck S, Miller A, Cole T, Sousa-Santos N, Cope A, Cizmeci D, Tolazzi M, Hwekwete E, Hannaman D, Kratochvil S, McKay PF, Chung AW, Kent SJ, Cook A, Scarlatti G, Abraham S, Combadiere B, McCormack S, Lewis DJ, Shattock RJ, Cheeseman HM, Day S, McFarlane L, Fleck S, Miller A, Cole T, Sousa-Santos N, Cope AV, Cizmeci D, Tolazzi M, Hwekwete E, Hannaman D, Kratochvil S, McKay P, Chung A, Kent S, Cook A, Scarlatti G, Abraham S, Combadiere B, McCormack S, Lewis D, Shattock Ret al., 2018, Combined Skin and Muscle DNA Priming Provides Enhanced Humoral Responses to a Human Immunodeficency Virus Type 1 Clade C Envelope Vaccine, Human Gene Therapy, Vol: 29, Pages: 1011-1028, ISSN: 1043-0342

© Copyright 2018, Mary Ann Liebert, Inc., publishers2018. Intradermal (i.d.) and intramuscular (i.m.) injections when administered with or without electroporation (EP) have the potential to tailor the immune response to DNA vaccination. This Phase I randomized controlled clinical trial in human immunodeficiency virus type 1-negative volunteers investigated whether the site and mode of DNA vaccination influences the quality of induced cellular and humoral immune responses following the DNA priming phase and subsequent protein boost with recombinant clade C CN54 gp140. A strategy of concurrent i.d. and i.m. DNA immunizations administered with or without EP was adopted. Subtle differences were observed in the shaping of vaccine-induced virus-specific CD4+ and CD8+ T cell-mediated immune responses between groups receiving: i.d.EP+ i.m., i.d. + i.m.EP, and i.d.EP+ i.m.EPregimens. The DNA priming phase induced 100% seroconversion in all of the groups. A single, non-adjuvanted protein boost induced a rapid and profound increase in binding antibodies in all groups, with a trend for higher responses in i.d.EP+ i.m.EP. The magnitude of antigen-specific binding immunoglobulin G correlated with neutralization of closely matched clade C 93MW965 virus and Fc-dimer receptor binding (FcγRIIa and FcγRIIIa). These results offer new perspectives on the use of combined skin and muscle DNA immunization in priming humoral and cellular responses to recombinant protein.

Journal article

Kratochvil S, McKay PF, Kopycinski JT, Bishop C, Hayes PJ, Muir L, Pinder CL, Cizmeci D, King D, Aldon Y, Wines BD, Hogarth PM, Chung AW, Kent SJ, Held K, Geldmacher C, Dally L, Santos NS, Cole T, Gilmour J, Fidler S, Shattock RJet al., 2017, A phase 1 human immunodeficiency virus vaccine Trial for cross-profiling the kinetics of serum and mucosal antibody responses to CN54gp140 modulated by two homologous prime-boost vaccine regimens, Frontiers in Immunology, Vol: 8, ISSN: 1664-3224

A key aspect to finding an efficacious human immunodeficiency virus (HIV) vaccine is the optimization of vaccine schedules that can mediate the efficient maturation of protective immune responses. In the present study, we investigated the effect of alternate booster regimens on the immune responses to a candidate HIV-1 clade C CN54gp140 envelope protein, which was coadministered with the TLR4-agonist glucopyranosyl lipid A-aqueous formulation. Twelve study participants received a common three-dose intramuscular priming series followed by a final booster at either 6 or 12 months. The two homologous prime-boost regimens were well tolerated and induced CN54gp140-specific responses that were observed in both the systemic and mucosal compartments. Levels of vaccine-induced IgG-subclass antibodies correlated significantly with FcγR engagement, and both vaccine regimens were associated with strikingly similar patterns in antibody titer and FcγR-binding profiles. In both groups, identical changes in the antigen (Ag)-specific IgG-subclass fingerprint, leading to a decrease in IgG1 and an increase in IgG4 levels, were modulated by booster injections. Here, the dissection of immune profiles further supports the notion that prime-boost strategies are essential for the induction of diverse Ag-specific HIV-1 responses. The results reported here clearly demonstrate that identical responses were effectively and safely induced by both vaccine regimens, indicating that an accelerated 6-month regimen could be employed for the rapid induction of immune responses against CN54gp140 with no apparent impact on the overall quality of the induced immune response. (This study has been registered at http://ClinicalTrials.gov under registration no. NCT01966900.)

Journal article

Cosgrove CA, Lacey CJ, Cope AV, Bartolf A, Morris G, Yan C, Baden S, Cole T, Carter D, Brodnicki E, Shen X, Joseph S, DeRosa SC, Peng L, Yu X, Ferrari G, Seaman M, Montefiori DC, Frahm N, Tomaras GD, Stöhr W, McCormack S, Shattock RJet al., 2016, Comparative immunogenicity of HIV-1 gp140 vaccine delivered by parenteral, and mucosal routes in female volunteers; MUCOVAC2, a randomized two centre study, PLOS One, Vol: 11, ISSN: 1932-6203

BackgroundDefining optimal routes for induction of mucosal immunity represents an important research priority for the HIV-1 vaccine field. In particular, it remains unclear whether mucosal routes of immunization can improve mucosal immune responses.MethodsIn this randomized two center phase I clinical trial we evaluated the systemic and mucosal immune response to a candidate HIV-1 Clade C CN54gp140 envelope glycoprotein vaccine administered by intramuscular (IM), intranasal (IN) and intravaginal (IVAG) routes of administration in HIV negative female volunteers. IM immunizations were co-administered with Glucopyranosyl Lipid Adjuvant (GLA), IN immunizations with 0.5% chitosan and IVAG immunizations were administered in an aqueous gel.ResultsThree IM immunizations of CN54 gp140 at either 20 or 100 μg elicited significantly greater systemic and mucosal antibodies than either IN or IVAG immunizations. Following additional intramuscular boosting we observed an anamnestic antibody response in nasally primed subjects. Modest neutralizing responses were detected against closely matched tier 1 clade C virus in the IM groups. Interestingly, the strongest CD4 T-cell responses were detected after IN and not IM immunization.ConclusionsThese data show that parenteral immunization elicits systemic and mucosal antibodies in women. Interestingly IN immunization was an effective prime for IM boost, while IVAG administration had no detectable impact on systemic or mucosal responses despite IM priming.

Journal article

Ma JK-C, Drossard J, Lewis D, Altmann F, Boyle J, Christou P, Cole T, Dale P, van Dolleweerd CJ, Isitt V, Katinger D, Lobedan M, Mertens H, Paul MJ, Rademacher T, Sack M, Hundleby PAC, Stiegler G, Stoger E, Twyman RM, Vcelar B, Fischer Ret al., 2015, Regulatory approval and a first-in-human phase I clinical trial of a monoclonal antibody produced in transgenic tobacco plants, Plant Biotechnology Journal, Vol: 13, Pages: 1106-1120, ISSN: 1467-7644

Journal article

Cosgrove CA, Lacey C, Cope AV, Bartolf A, Morris G, Yan C, Baden S, Cole T, Carter D, Brodnicki E, Stoehr W, McCormack S, Shattock RJet al., 2013, A Phase I Clinical Trial of an HIV-1(CN54), Clade C, Trimeric Envelope Vaccine Delivered by Parenteral, Nasal and Vaginal Routes of Immunisation, Conference on AIDS Vaccine, Publisher: MARY ANN LIEBERT, INC, Pages: A9-A9, ISSN: 0889-2229

Conference paper

Lewis DJ, Fraser CA, Mahmoud AN, Wiggins RC, Woodrow M, Cope A, Cai C, Giemza R, Jeffs SA, Manoussaka M, Cole T, Cranage MP, Shattock RJ, Lacey CJet al., 2011, Phase I randomised clinical trial of an HIV-1(CN54), clade C, trimeric envelope vaccine candidate delivered vaginally, PLoS ONE, Vol: 6, ISSN: 1932-6203

We conducted a phase 1 double-blind randomised controlled trial (RCT) of a HIV-1 envelope protein (CN54 gp140) candidate vaccine delivered vaginally to assess immunogenicity and safety. It was hypothesised that repeated delivery of gp140 may facilitate antigen uptake and presentation at this mucosal surface. Twenty two healthy female volunteers aged 18–45 years were entered into the trial, the first receiving open-label active product. Subsequently, 16 women were randomised to receive 9 doses of 100 µg of gp140 in 3 ml of a Carbopol 974P based gel, 5 were randomised to placebo solution in the same gel, delivered vaginally via an applicator. Participants delivered the vaccine three times a week over three weeks during one menstrual cycle, and were followed up for two further months. There were no serious adverse events, and the vaccine was well tolerated. No sustained systemic or local IgG, IgA, or T cell responses to the gp140 were detected following vaginal immunisations. Repeated vaginal immunisation with a HIV-1 envelope protein alone formulated in Carbopol gel was safe, but did not induce local or systemic immune responses in healthy women.

Journal article

Donnelly L, Curran RM, Tregoning JS, McKay PF, Cole T, Morrow RJ, Kett VL, Andrews GP, Woolfson AD, Malcolm RK, Shattock RJet al., 2011, Intravaginal immunization using the recombinant HIV-1 clade-C trimeric envelope glycoprotein CN54gp140 formulated within lyophilized solid dosage forms, Vaccine, Vol: 29, Pages: 4512-4520, ISSN: 1873-2518

Vaccine-mediated prevention of primary HIV-1 infection at the heterosexual mucosal portal of entry may be facilitated by highly optimised formulations or drug delivery devices for intravaginal (i.vag) immunization. Previously we described hydroxyethylcellulose (HEC)-based rheologically structured gel vehicles (RSVs) for vaginal immunization of an HIV-1 vaccine candidate, a soluble recombinant trimeric HIV-1 clade-C envelope glycoprotein designated CN54gp140. Here we investigated the efficacy of lyophilized solid dosage formulations (LSDFs) for prolonging antigen stability and as i.vag delivery modalities. LSDFs were designed and developed that upon i.vag administration they would reconstitute with the imbibing of vaginal fluid to mucoadhesive, site-retentive semi-solids. Mice were immunized with lyophilized equivalents of (i) RSVs, (ii) modified versions of the RSVs more suited to lyophilization (sodium carboxymethyl cellulose (NaCMC)-based gels) and (iii) Carbopol® gel, all containing CN54gp140. NaCMC-based LSDFs provided significantly enhanced antigen stability compared to aqueous-based RSVs. Rheological analysis indicated the NaCMC-based LSDFs would offer enhanced vaginal retention in woman compared to more conventional vaginal gel formulations. All LSDFs were well tolerated in the mouse model. Following i.vag administration, all LSDFs boosted systemic CN54gp140-specific antibody responses in sub-cutaneously primed mice. Induction of CN54gp140-specific antibody responses in the female genital tract was evident. Of all the LSDFs the fastest releasing which was lyophilized Carbopol® gel elicited immune responses comparable to buffer instillation of antigen suggesting that rather than slower sustained release, initial high burst release from the LSDFs may suffice. The boosting of specific immune responses upon i.vag administration indicates that LSDFs are viable mucosal vaccine delivery modalities promoting antigen stability and facilitating intimate exposur

Journal article

Cranage MP, Fraser CA, Cope A, Mckay PF, Seaman MS, Cole T, Mahmoud AN, Hall J, Giles E, Voss G, Page M, Almond N, Shattock RJet al., 2011, Antibody responses after intravaginal immunisation with trimeric HIV-1(CN54) clade C gp140 in Carbopol gel are augmented by systemic priming or boosting with an adjuvanted formulation, Vaccine, Vol: 29, Pages: 1421-1430, ISSN: 0264-410X

Optimum strategies to elicit and maintain antibodies at mucosal portals of virus entry are critical for the development of vaccines against human immunodeficiency virus (HIV). Here we show in non-human primates that a novel regimen of repeated intravaginal delivery of a non-adjuvanted, soluble recombinant trimeric HIV-1(CN54) clade C envelope glycoprotein (gp140) administered in Carbopol gel can prime for B-cell responses even in the absence of seroconversion. Following 3 cycles of repeated intravaginal administration, throughout each intermenses interval, 3 of 4 macaques produced or boosted systemic and mucosally-detected antibodies upon intramuscular immunisation with gp140 formulated in AS01 adjuvant. Reciprocally, a single intramuscular immunisation primed 3 of 4 macaques for antibody boosting after a single cycle of intravaginal immunisation. Virus neutralising activity was detected against clade C and clade B HIV-1 envelopes but was restricted to highly neutralisation sensitive pseudoviruses. (C) 2010 Elsevier Ltd. All rights reserved.

Journal article

Cranage MP, Fraser CA, Stevens Z, Huting J, Chang M, Jeffs SA, Seaman MS, Cope A, Cole T, Shattock RJet al., 2010, Repeated vaginal administration of trimeric HIV-1 clade C gp140 induces serum and mucosal antibody responses, MUCOSAL IMMUNOLOGY, Vol: 3, Pages: 57-68, ISSN: 1933-0219

Journal article

Cranage M, Fraser C, Cope A, McKay PF, Elsley W, Page M, Mahmoud AN, DaCosta K, Voss G, Fletcher P, Armanasco N, Cole T, Almond N, Shattock RJet al., 2009, Intravaginal administration of HIV-1 ZM96 gp140 augments systemic and mucosal antibody responses following systemic priming with adjuvanted protein., Europrise: Rational Design of HIV Vaccines and Microbicides

Conference paper

Lewis DJ, Lacey CJ, Jeffs S, Cole T, Fraser C, Wiggins R, Woodrow M, Cope A, Cai C, Giemza E, Mahmhoud A, Katinger D, Cranage M, Shattock Ret al., 2009, Phase I safety and immunogenicity randomised controlled trial of a vaginal gp140 vaccine, RETROVIROLOGY, Vol: 6, ISSN: 1742-4690

Journal article

Cole TE, Hong YG, Brasier CM, Buck KWet al., 2000, Detection of an RNA-dependent RNA polymerase in mitochondria from a mitovirus-infected isolate of the Dutch elm disease fungus, Ophiostoma novo-ulmi, VIROLOGY, Vol: 268, Pages: 239-243, ISSN: 0042-6822

Journal article

Hong YG, Dover SL, Cole TE, Brasier CM, Buck KWet al., 1999, Multiple mitochondrial viruses in an isolate of the Dutch elm disease fungus Ophiostoma novo-ulmi, VIROLOGY, Vol: 258, Pages: 118-127, ISSN: 0042-6822

Journal article

Cole TE, Muller BM, Hong Y, Brasier CM, Buck KWet al., 1998, Complexity of virus-like double-stranded RNA elements in a diseased isolate of the Dutch elm disease fungus, Ophiostoma novo-ulmi, JOURNAL OF PHYTOPATHOLOGY-PHYTOPATHOLOGISCHE ZEITSCHRIFT, Vol: 146, Pages: 593-598, ISSN: 0931-1785

Journal article

Hong YG, Cole TE, Brasier CM, Buck KWet al., 1998, Novel structures of two virus-like RNA elements from a diseased isolate of the Dutch elm disease fungus, Ophiostoma novo-ulmi, VIROLOGY, Vol: 242, Pages: 80-89, ISSN: 0042-6822

Journal article

Walker A, Cole T, Torney K, Gray Jet al., 1997, Chromosome locations of five genes encoding photosynthetic electron transfer proteins in Arabidopsis thaliana, Photosynthesis Research, ISSN: 0166-8595

Journal article

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